Pulmonary fibrosis (PF) is an insidious fibroproliferative condition characterized by a gradual replacement of normal parenchyma cells with fibrous, connective, matrix macromolecules (e.g., collagens, fibronectins and proteoglycans) on and within the lungs, usually at sites of injury or infection. The excessive formation of fibrous tissue, resulting from the activation and proliferation of fibroblast cells, destructs normal lung structure and function. For instance, the accumulation of fibrous tissue thickens alveolar walls, obliterates air space, and causes epithelial injury or even alveolar collapse. As a result, patients suffering from pulmonary fibrosis experience a varying degree of exertional dyspnea, and in late stages, orthopnea, cyanosis, and respiratory failure1. Median survival of pulmonary fibrosis is about 2-3 years and approximately 65% of patients die within 5 years of diagnosis.
Irradiation (IR) therapy, the most common treatment regime for tumor or cancer, may cause lung injury and ultimately lead to IR-induced pneumopathy including pulmonary fibrosis1. Risk of IR-induced pneumopathy further increases with concurrent administration of cytotoxic chemotherapeutic agents. IR-induced pneumopathy not only causes devastating effects on the quality of patient life, but sometimes can be even more life-threatening than the primary tumor or cancer1. Consequently, the risk of IR-induced pneumopathy, such as pulmonary fibrosis, has become a major dose-limiting factor and sometimes even prevents the use of irradiation therapy.
Currently, there is no cure for pulmonary fibrosis. While anti-inflammatory or pulmonary protective agents may alleviate symptoms of pulmonary fibrosis or improve patient life, they cannot halt disease progression. Common drugs for pulmonary fibrosis include amifostine, celebrex, and dexamethasone. While amifostine achieves certain cytoprotective effects against IR-induced pulmonary injury2, it must be administered to patients 30 minutes prior to lung injury, and thus, cannot prevent or treat accidental lung injury. Celebrex, a widely used anti-inflammatory agent, has not been reported as effective for treatment of pneumonitis or pulmonary fibrosis. Dexamethasone is an anti-inflammatory steroid drug, and can cause serious side effects during long-term use. Further, the present inventors have observed that dexamethasone may result in worsening of pulmonary fibrosis, leading to lung failure or even earlier death as compared to the non-treated controls. Therefore, therapeutic agents with improved efficacy and safety are urgently needed. Traditional Chinese medicine has been practiced by the Chinese people for 2-3 millennia.
It deals with pathology, and diagnosis, treatment and prevention of diseases. Chinese medicinal materials have been recorded in various pharmacopoeia. One of the classical references for medicinal herbs is Ben Cao Gang Mu written by Li, Shizhen in the late 14th Century. The book contains about 2,500 items of herbs and other products including animals and minerals.
Liquorice (Glycyrrhiza glabra) has a long and diverse history of medicinal use in East Asian countries. Its root has been used as therapeutics for dermatitis and peptic ulcers. Glycyrrhizic acid (also known as Glycyrrhizin) (GLA) is a naturally-occurring compound that can be isolated from root of Glycyrrhiza species including Liquorice (Glycyrrhiza glabra). GLA is widely used as a flavoring agent in the United States and Europe, and has been approved by the State Food and Drug Administration of China for the treatment of chronic hepatitis and cirrhosis. Glycyrrhetinic acid (GA), a pentacyclic triterpenoid derivative that forms the functional motif of glycyrrhizic acid (GLA), has been used for the treatment of inflammation, peptic ulcer and infection. GA, GLA and related compounds, however, have not previously been reported to play any role in the treatment of pulmonary fibrosis.